In order to evaluate the role of LCAT in HDL metabolism, and atherosclerosis we have generated transgenic mice overexpressing hLCAT at plasma levels 100 fold higher than control (1 ug/ml) mice. Compared to 24 age and sex-matched siblings, transgenic mice had elevated plasma TC (133-237% of NL), CE (141-267% of NL) and HDL-C (123-209% of NL) but similar plasma levels of triglycerides, PL, B-containing lipoproteins, apoA-I and apoA-II. FPLC analysis of hLCAT TG plasma revealed larger sized HDL particles enriched in CE and PL. Thus, LCAT modulates the composition and heterogeneity as well as the concentrations of HDL in mice. Age/sex matched transgenic (M=7, F=8) and control (M=14, F=13) animals were then placed on a high chol-fat (HF) diet for 21 d to investigate the potential role of LCAT in modulating dietary responses. Pre-diet lipid values (mg/dl) in controls were TC=97+/-11, HDL=72+/-10 and in transgenics were TC=121 +/-16, HDL-C=84 +/-17. Post-diet lipid values in controls were TC=290+/-55, HDL= 85+/-15, and in transgenics were TC=313+/-83, HDL=115+/-27. Thus, on the HF diet transgenic mice had significantly higher (p<0.05) HDL-C as well as reduced TC/HDL ratios than controls, without differences in Tg, PL, CE, LCAT mass and activity. FPLC analysis of transgenic mouse plasma revealed significant increases in HDL-C, CE and PL with reciprocal decreases in IDL/LDL-C, CE and PL, demonstrating LCAT-mediated modulation of plasma lipids in response to a dietary challenge. In order to evaluate the effect of overexpressing the human LCAT gene on diet-induced atherosclerosis control (N=19)and LCAT transgenic (N=18) C57Bl mice were analyzed 16 weeks after initiation of a high fat-diet. Analysis of mean aortic lesion size revealed no differences between control and transgenic mice. These findings indicate that in this animal model with a deficiency of CETP, LCAT overexpression does not protect against the development of diet-induced atherosclerosis.